Cytomegalovirus (CMV) is a member of the herpes virus family, other well-known members of which include herpes simplex virus, types I and II, Epstein-Barr virus and Varicella Zoster virus. Although these viruses are related taxonomically as double-stranded DNA viruses, each manifests in a clinically distinct manner. In the case of CMV, medical conditions arising from congenital infection include jaundice, respiratory distress and convulsive seizures which may result in mental retardation, neurologic disability or death. Infection in adults is frequently asymptomatic, but may manifest as mononucleosis, hepatitis, pneumonitis or retinitis, particularly in immunocompromised patients such as AIDS sufferers, chemotherapy patients and organ transplant patients undergoing tissue rejection therapy.
A variety of drugs have been developed to treat herpesvirus infection, including natural occurring proteins and synthetic nucleoside analogs. For example, the natural antiviral protein, interferon, has been used in the treatment of herpesvirus infections, as have the nucleoside analogs, cytosine-arabinoside, adenine arabinoside, iodoxyuridine and acyclovir, which is presently the treatment of choice for herpes simplex type I infection.
Unfortunately, drugs such as acyclovir that have proven effective to treat infection by certain herpesviruses are not sufficiently effective to treat CMV. And, drugs currently used to treat CMV infection, such as 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (ganciclovir, DHPG) and phosphonoformic acid (foscarnet), lack the acceptable side effect and safety profiles of the drugs approved for other treatment of other herpesviruses. Moreover, such drugs are ineffective to treat certain strains of CMV that have acquired drug resistance. Thus, despite recent advances in the development of anti-herpesvirus drugs, there remains a need for therapeutic agents effective to treat CMV infection.
In co-pending patent application WO92/07871 (published 14 May 1992), there are disclosed oligopeptides that are effective to control replication of the human immunodeficiency virus (HIV). In co-pending patent application WO93/21941 (published 11 Nov. 1993), there is disclosed the discovery that these oligopeptides are also effective to prevent replication of certain viruses within the herpesvirus family, particularly the herpes simplex viruses. Further investigation of the anti-viral properties of these oligopeptides has now surprisingly revealed their ability to control replication of cytomegalovirus, including human CMV. It has now also been discovered that these oligopeptides act synergistically with current anti-CMV drugs, particularly ganciclovir, to control replication of CMV.
Accordingly, it is an object of the present invention to provide a method useful to control CMV replication, and further to provide a method for controlling cytomegaloviral infection in a mammal.
It is another object of the present invention to provide pharmaceutical compositions and combinations useful to treat cytomegaloviral infection.